EP2560955B1 - Novel benzamide derivatives - Google Patents

Novel benzamide derivatives Download PDF

Info

Publication number: EP2560955B1
Authority: EP; European Patent Office
Prior art keywords: methyl; chloro; piperidin; amino; compound
Prior art date: 2010-04-23
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

EP11772189.4A

Other languages

German (de)

English (en)

French (fr)

Other versions

EP2560955A2 (en

EP2560955A4 (en

Inventor

Soon-Hoe Kim

Weon-Bin Im

Sung-Hak Choi

Sun-Ho Choi

Ju-Hee Sohn

Hyun-Jung Sung

Mi-Yeon Kim

Kang-Hun Cho

Tae-Kyoung Sohn

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Dong A Pharmaceutical Co Ltd

Original Assignee

Dong A Pharmaceutical Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2010-04-23

Filing date

2011-04-18

Publication date

2016-06-29

2011-04-18 Application filed by Dong A Pharmaceutical Co Ltd filed Critical Dong A Pharmaceutical Co Ltd

2013-02-27 Publication of EP2560955A2 publication Critical patent/EP2560955A2/en

2013-09-11 Publication of EP2560955A4 publication Critical patent/EP2560955A4/en

2016-06-29 Application granted granted Critical

2016-06-29 Publication of EP2560955B1 publication Critical patent/EP2560955B1/en

Status Active legal-status Critical Current

2031-04-18 Anticipated expiration legal-status Critical

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

Definitions

the present invention relates to a novel benzamide derivative of formula 1 which will be illustrated hereinafter or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a 5-HT 4 receptor agonist containing the same as an active ingredient.
Serotonin is a neurotransmitter widely distributed throughout the body. Seven subtypes of serotonin are currently known. In particular, great attention has been focused on the elucidation of a 5-HT 4 receptor and the confirmation of pharmaceutical action thereof.
5-HT 4 receptor agonists are found to be therapeutically effective for the treatment of various disease conditions such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disorder, cardiac failure, cardiac arrhythmia, diabetes and apnea syndrome (See Tips, 1992, 13, 141 ; Ford A.P.D.W. et al., Med. Res. Rev., 1993, 13.
5-HT 4 receptor agonists Despite extensive uses of 5-HT 4 receptor agonists, there are little 5-HT 4 receptor agonist compounds that are currently clinically used. To this end, there is a need for a 5-HT 4 receptor agonist which is capable of exhibiting excellent medicinal effects while having minimum adverse side effects.
Benzamide derivatives have several prominent pharmacological actions. These excellent pharmacological activities of the benzamide derivatives are due to their effects on the nervous system which is controlled by serotonin that is a neurotransmitter.
serotonin that is, the pharmacological action of benzamide derivatives has been broadly involved in a variety of diseases and conditions for many years. Further, a great deal of study and research has focused on production and storage sites of serotonin as well as the location of serotonin receptors in order to determine the relationship between the location of serotonin receptors and various disease states or conditions in humans.
Cisapride which is a typical 5-HT 4 receptor agonist, is one of benzamide derivatives.
U.S. Patent Nos. 4,962,115 , 5,057,525 and 5,137,896 disclose N-(3-hydroxy-4-piperidinyl)benzamides including cisapride. These compounds are known to stimulate gastrointestinal motility. Further, U.S. Patent No. 5,864,039 discloses benzamide derivatives.
the inventors of the present invention succeeded in the synthesis of novel benzamide derivatives which exhibit an agonistic activity via strong binding with a 5-HT 4 receptor and good gastrointestinal absorption and which are capable of minimizing adverse side effects.
the present invention has been completed based on this finding.
the present invention is intended to provide a novel benzamide derivative or a pharmaceutically acceptable salt thereof and a method for preparing the same.
the present invention is intended to provide a 5-HT 4 receptor agonist containing a novel benzamide derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
the present invention provides a novel benzamide derivative represented by formula 1(a compound represented by formula 1): wherein m represents an integer of 1 to 5; and Q represents a heteroaromatic ring, wherein the heteroramatic ring is independently substituted by 0, 1, 2, or 3 substituents selected from C 1-4 alkyl, C 1-4 alkoxy, hydroxy and halogen, the heteroaromatic ring being a C 1-12 aromatic ring or C 1-12 bicylic aromatic ring independently containing 1 to 4 heteroatoms selected from N, O or S; or a pharmaceutically acceptable salt thereof.
alkyl refers to a linear or branched, monovalent saturated C 1 -C 20 hydrocarbon radical containing only carbon atoms and hydrogen atoms.
alkyl radical include methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, pentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, 2-ethylhexyl, octyl, and dodecyl.
alkoxy refers to a radical-OR wherein R represents alkyl as defined above.
alkoxy radical include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, 3-methylpentoxy, 4-methylpentoxy, n-hexoxy, and 2-ethylhexoxy.
heteroaromatic ring refers to an aromatic ring or bicyclic aromatic ring contains 1 to 4 hetero atoms selected from O, N or S.
heteroaromatic ring examples include pyrrole, imidazole, triazole, tetrazole, pyridine, pyrimidine, oxazole, oxadiazole, isoxazole, indole, quinoline and benzofuran.
the pharmaceutically acceptable salt may be an acid addition salt with an acceptable free acid.
the free acid may be an inorganic or organic acid.
the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.
the organic acid include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid, and aspartic acid.
the compound of formula 1 or a pharmaceutically acceptable salt thereof may exhibit polymorphism and may also be present in the form of a solvate (e.g., hydrate, etc).
the present invention relates to a novel benzamide derivative selected from the group consisting of the following compounds:
the present invention provides a method for preparing a benzamide derivative of formula 1 or a pharmaceutically acceptable salt thereof.
the present invention provides a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, which includes reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 3 in the presence of a base to introduce the compound of formula 3 at an amine of the 1-position of the piperidine ring of the compound of formula 2 or the pharmaceutically acceptable salt thereof, thereby preparing the compound of formula 1 (hereinafter, referred to as "Preparation Method 1").
m and Q are as defined in formula 1, and Y represents a halogen atom or C 1 -C 4 alkylsulfonate.
the base is preferably selected from potassium carbonate, potassium iodide, triethylamine, diisopropylethylamine and their mixture
the solvent may be dimethylformamide, dimethylacetamide, acetone, 1,4-dioxane or the like, and the reaction may be carried out at a temperature of 50°C to 140°C.
the present invention provides a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, which includes reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 11 in the presence of a reducing agent to prepare the compound of formula 1 (hereinafter, referred to as "Preparation Method 2").
the reducing agent is preferably sodium cyanoborohydride and acetic acid, or sodium borohydride
the solvent may be a C 1 -C 6 lower alcohol, preferably ethanol or methanol, and the reaction may be carried out at a temperature of 50°C to 100°C.
the compound of formula 2 or the pharmaceutically acceptable salt thereof in Preparation Method 1 or Preparation Method 2 of the present invention may be prepared by the following steps of:
Y represents a halogen atom or C 1 -C 4 alkylsulfonate
Z represents C 1 -C 4 alkyl
the amine protecting group-introducing reagent of Step (1) refers to a reagent used conventionally for the protection of an amine in order to prevent an amine group from participating in the reaction.
a reagent is preferably selected from di-t-butyl dicarbonate or ethyl chloroformate in the presence of a tertiary amine such as triethylamine.
the solvent may be a C 1 -C 6 lower alcohol.
the reaction may be carried out with gradual elevation of a temperature from 0°C to room temperature.
the C 1 -C 4 alkyl sulfonyl halide of Step (2) is preferably methane sulfonyl chloride, methane sulfonyl bromide or methane sulfonyl fluoride, the tertiary amine may be triethylamine, diisopropylethylamine or the like, and the solvent may be dichloromethane, chloroform, or the like.
the reaction may be carried out with gradual elevation of a temperature from 0°C to room temperature.
the solvent used in Step (3) may be dimethylformamide, dimethylacetamide or the like, and the reaction temperature may be in the range of 80 to 140°C.
the reducing agent used in Step (4) is preferably triphenylphosphine or lithium aluminum hydride, and the solvent used may be tetrahydrofuran.
the reaction may be carried out with gradual elevation of a temperature from 0°C to room temperature or may be carried out in the range of 60 to 80°C.
the amide bond formation-inducing reagent used in Step (5) refers to a common reagent which is used by a person of ordinary skill and which is used to remove water generated after the reaction, in order to promote the amide bond between carboxylic acid and an amine, or is used to activate an amine or carboxylic acid.
Examples of the amide bond formation-inducing reagent include N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of a base, ethyl chloroformate in the presence of a base, and carbodiimidazole in the absence of a base.
examples of the base used in combination with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or ethyl chloroformate include triethylamine and diisopropylethylamine.
the reaction solvent used may be dimethyl formamide, dimethyl acetamide, dichloromethane, or the like. The reaction may be carried out with gradual elevation of a temperature from 0°C to room temperature.
the base or acid of Step (6) refers to a base or acid which is conventionally used to deprotect the carbamate of an amine, and examples thereof include hydrochloric acid, trifluoroacetic acid, and potassium hydroxide.
the reaction solvent used may be 1,4-dioxane, dichloromethane, C 1 -C 6 lower alcohol, or the like. The reaction may be carried out with gradual elevation of a temperature from 0°C to room temperature.
the compound of formula 3 in the present invention may be prepared according to the method as in Reaction Scheme 1 or Reaction Scheme 2 provided below.
the substituents Q and m are as defined in formula 1, and both of Y and Y' represent halogen atoms which are preferably different from each other, for example, one of Y and Y' represents chloro (Cl) and the other one of Y and Y' represents bromo (Br).
the reaction of Reaction Scheme 1 may be carried out in the presence of a strong base such as lithium hydride, sodium hydride or potassium hydride, in an organic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, at a reaction temperature of 0 to 40°C for 1 to 24 hours.
a strong base such as lithium hydride, sodium hydride or potassium hydride
organic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran
Y represents a C 1 -C 4 alkyl sulfonyl halide or a halogen atom
Y" represents a hydroxyl group
Y'" represents a halogen atom selected from Cl, Br or I.
the first step reaction of Reaction Scheme 2 may be carried out in the presence of a base such as potassium carbonate and potassium iodide, in a solvent such as 1,4-dioxane or acetone, at a temperature of 60 to 120°C for 1 to 12 hours.
a base such as potassium carbonate and potassium iodide
a solvent such as 1,4-dioxane or acetone
the second step reaction of Reaction Scheme 2 may be carried out by reacting Y"-(CH 2 )m-Q with a C 1 -C 4 alkyl sulfonyl halide (for example, sulfonyl chloride, methane sulfonyl bromide, or methane sulfonyl fluoride) in the presence of a base such as triethylamine or diisopropylethylamine, in an organic solvent such as dichloromethane or chloroform, at a reaction temperature of 0 to 40°C for 1 to 24 hours.
a base such as triethylamine or diisopropylethylamine
the second step reaction of Reaction Scheme 2 may be carried out under the conventionally known reaction conditions for substitution of the hydroxyl group of Y"-(CH 2 )m-Q with a halogen.
the reaction may be carried out in the presence of one species selected from N-bromosuccinimide or carbon tetrabromide and triphenylphosphine, in an organic solvent such as dichloromethane, at a reaction temperature of 0 to 40°C for 1 to 24 hours.
the acid addition salt of a free base of a compound represented by formula 1 may be prepared using a conventional method known in the art, for example by mixing a free base of the compound of formula 1 with an appropriate acid in a suitable solvent, which is then followed by evaporation to form a salt or the addition of a non-solvent to precipitate a salt.
a method which involves treating a solution or suspension of a free base with a desired acid in a reaction-inert solvent, followed by concentration under reduced pressure or crystallization or any standard chemical manipulation to form a desired salt.
a hydrochloride of the compound of formula 1 may be prepared by dissolving a free base of the compound of formula 1 in a C 1 -C 4 alcohol solvent such as ethanol or methanol, adding hydrochloric acid thereto, and then stirring the mixture at room temperature.
a C 1 -C 4 alcohol solvent such as ethanol or methanol
the present invention provides a 5-HT 4 receptor agonist containing a compound of formula 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
the 5-HT 4 receptor agonist may be a composition for use in the prevention or treatment of a disease selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disorder, cardiac failure, cardiac arrhythmia, diabetes or apnea syndrome.
a disease selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease,
the 5-HT 4 receptor agonist of the present invention may further contain one or more active ingredients exhibiting an identical or similar function, in addition to the compound of formula 1 in accordance with the present invention or a pharmaceutically acceptable salt thereof.
the agonist or composition of the present invention may be formulated into a variety of dosage forms by further inclusion of one or more pharmaceutically acceptable carriers in combination with the above-mentioned active ingredient.
pharmaceutically acceptable carriers include saline, sterile water, Ringer's solution, buffered saline, a dextrose solution, a maltodextrin solution, glycerol, and ethanol. These materials may be used alone or in any combination thereof. If necessary, other conventional additives may be added such as an antioxidant, a buffer and a bacteriostatic agent.
a diluent, a dispersant, a surfactant, a binder and a lubricant may be additionally added to prepare an injectable formulation such as aqueous solution, suspension or emulsion, or an oral formulation such as pill, capsule, granule or tablet.
an injectable formulation such as aqueous solution, suspension or emulsion
an oral formulation such as pill, capsule, granule or tablet.
the desired dosage form may be preferably formulated depending on diseases to be treated and ingredients, using any appropriate method known in the art, as disclosed in " Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA .
the content of the compound of formula 1 in accordance with the present invention or a pharmaceutically acceptable salt thereof in the formulation may be in the range of 1 to 95% by weight and preferably 1 to 70% by weight.
the agonist or composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally) or orally, depending on desired applications.
the dose of the active ingredient may vary depending on various factors such as weight, age, sex, health status and dietary habits of patients, administration times and routes, excretion rates, and severity of diseases.
the benzamide derivative of the present invention may be administered at a dose of 1 to 1000 ⁇ g/kg, preferably about 10 to 500 ⁇ g/kg and more preferably about 83 to 167 ⁇ g/kg, once or several times a day.
the present invention provides a compound for use in the prevention, treatment or alleviation of a disease due to attenuated efficacy of a 5-HT 4 receptor, wherein the compound is of formula 1 in accordance with the present invention or a pharmaceutically acceptable salt thereof.
the 5-HT 4 receptor agonist may be a composition for use in the prevention or treatment of a disease selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disorder, cardiac failure, cardiac arrhythmia, diabetes or apnea syndrome.
a disease selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, emesis, migraine, neurological disease,
the 5-HT 4 receptor agonist of the present invention may be used alone or in combination with methods employing surgical operation, hormone therapy, medication therapy and biological response modifiers.
Benzamide derivatives of the present invention have a superior affinity for 5-HT 4 receptors, a capability to reduce a gastric emptying time and a low toxicity, and consequently are therapeutically effective for the treatment of a variety of diseases associated with 5-HT 4 receptors.
reagents used hereinafter were purchased from Aldrich Korea, Acros, Lancaster, TCI, etc., and 1 H NMR experiments were performed using a Varian 400MHz spectrometer.
Step 1 Preparation of tertiary butyl 4-(hydroxymethyl)piperidine-1-carboxylate (compound of formula 5)
Step 3 Preparation of tertiary butyl 4-(azidomethyl)piperidine-1-carboxylate (compound of formula 7)
Step 4 Preparation of tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (compound of formula 8)
a 1,2,4-triazole sodium salt (5g, 54.91mmol) was dissolved in dimethylformamide (50mL) and the solution was cooled to 0°C. Then, sodium hydride (60%, 2.86g, 71.38mmol) was added thereto, followed by stirring for 30 minutes. 1-bromo-3-chloropropane (6.5mL, 65.89mmol) was added thereto, followed by stirring at room temperature for 12 hours, and the reaction was terminated with the addition of an ammonium chloride saturated solution. After extraction with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (2.77g, 35%).
1-(3-chloropropyl)-tetrazole was prepared using 1H-tetrazole and 1-bromo-3-chloropropane as starting materials of ⁇ Example 1-2>, and then the title compound (186mg) was obtained using 1-(3-chloropropyl)-tetrazole and 4-amino-5-chloro-2-methoxy-(piperidin-4-ylmethyl)benzamide hydrochloride as starting materials of ⁇ Example 1-3>.
1-(3-chloropropyl)-indole was prepared using indole and 1-bromo-3-chloropropane as starting materials of ⁇ Example 1-2>, and then the title compound (26mg) was obtained using 1-(3-chloropropyl)-indole and
1-(3-chloropropyl)-2-methylimidazole was prepared using 2-methylimidazole and 1-bromo-3-chloropropane as starting materials of ⁇ Example 1-2>, and then the title compound (226mg) was obtained using 1-(3-chloropropyl)-2-methylimidazole and 4-amino-5-chloro-2-methoxy-(piperidin-4-ylmethyl)benzamide hydrochloride as starting materials of ⁇ Example 1-3>.
1-(5-chloropentyl)-indole was prepared using indole and 1-bromo-5-chloropentane as starting materials of ⁇ Example 1-2>, and then the title compound (250mg) was obtained using 1-(5-chloropentyl)-indole and 4-amino-5-chloro-2-methoxy-(piperidin-4-ylmethyl)benzamide hydrochloride as starting materials of ⁇ Example 1-3>.
1-(5-chloropentyl)-1,2,3-triazole was prepared using 1,2,3-triazole and 1-bromo-5-chloropentane as starting materials of ⁇ Example 1-2>, and then the title compound (225mg) was obtained using 1-(5-chloropentyl)-1,2,3-triazole and 4-amino-5-chloro-2-methoxy-(piperidin-4-ylmethyl)benzamide hydrochloride as starting materials of ⁇ Example 1-3>.
1,2,3-triazole (2g, 28.96mmol) was dissolved in 1,4-dioxane (40mL), and potassium carbonate (8g, 57.92mmol), potassium iodide (962mg, 5.79mmol) and 3-bromopropanol (3.3mL, 43.43mmol) were added thereto, followed by stirring at 100°C for 3 hours. After the reaction was completed, the reactants were cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (2.5g, 68%).
Step 3 Preparation of N- ((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-metho xybenzamide
Indole-3-acetic acid (5g, 28.54mmol) was dissolved in diethyl ether (100mL) and the solution was cooled to 0°C. Lithium aluminum hydride (1.19g, 31.39mmol) was added thereto, followed by stirring for 4 hours. The reaction was terminated with the addition of water and a 10% sodium hydroxide solution. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (1.24g, 27%).
Step 2 Preparation of 3-(2-bromoethyl)-indole (compound of formula 3)
the binding affinity of the compounds for a human 5-HT 4 receptor was assayed according to the method as disclosed in the literature [ Wyngaert et al., Journal of Neurochemistry, (1997) 69, 1810-1819 ].
COS-7 cells expressing the human 5-HT 4 receptor were constructed and homogenized to obtain membrane homogenates which were then used in binding assay experiments.
the membrane homogenates were respectively mixed and incubated with different concentrations of test materials and [H3]-GR113808 (Amersham Biosciences).
the concentrations of the individual test materials were set to 4 ⁇ M, 1 ⁇ M, 0.25 ⁇ M, and 0.0625 ⁇ M, respectively, and the concentration of [H3]-GR113808 was set to 0.595nM.
the compounds of the present invention inhibited specific binding of the radioligand to the 5-HT 4 receptor at a concentration similar to or lower than that of cisapride as a control, thus representing that the inventive compounds have a strong binding affinity for 5-HT 4 receptor.
the minimum lethal dose (MLD, mg/kg) of the individual compounds was investigated by the observation of the mortality, body weight, clinical symptoms and the like of animals over the entire experimental period of 2 weeks. The results are given in Table 3 below.
Example 3 Compounds Minimum lethal dose (MLD, mg/kg) Example 1 >1000 Example 2 >1000 Example 3 >1000 Example 4 >1000 Example 5 >1000 Example 6 >1000 Example 7 >1000 Example 8 >1000 Example 9 >1000 Example 10 >1000 Example 11 >1000 Example 12 >1000 Example 15 >1000
the binding affinity of the compounds for the human ether-a-go-go-related gene (hERG) potassium (K+) channel which is associated with cardiac QT prolongation was assayed in MDS Pharma Service (Catalog No. 265900).
Membrane homogenates were obtained from mammalian HEK-293 cells expressing the hERG potassium channel and then used in the binding assay experiment.
the membrane homogenates were respectively mixed and incubated with 10 ⁇ M of test materials and 1.5nM of [H3]-Astemizole (Perkin Elmer). After the incubation was completed, the radioactivity bound to the hERG K+ channel was counted.

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Diabetes (AREA)
Pain & Pain Management (AREA)
Cardiology (AREA)
Pulmonology (AREA)
Heart & Thoracic Surgery (AREA)
Endocrinology (AREA)
Obesity (AREA)
Hematology (AREA)
Rheumatology (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Emergency Medicine (AREA)
Nutrition Science (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Hydrogenated Pyridines (AREA)
Pyridine Compounds (AREA)

EP11772189.4A 2010-04-23 2011-04-18 Novel benzamide derivatives Active EP2560955B1 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
KR1020100038039A KR101180174B1 (ko)	2010-04-23	2010-04-23	신규한 벤즈아미드 유도체
PCT/KR2011/002759 WO2011132901A2 (en)	2010-04-23	2011-04-18	Novel benzamide derivatives

Publications (3)

Publication Number	Publication Date
EP2560955A2 EP2560955A2 (en)	2013-02-27
EP2560955A4 EP2560955A4 (en)	2013-09-11
EP2560955B1 true EP2560955B1 (en)	2016-06-29

Family

ID=44834616

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP11772189.4A Active EP2560955B1 (en)	2010-04-23	2011-04-18	Novel benzamide derivatives

Country Status (20)

Country	Link
US (1)	US9221790B2 (ru)
EP (1)	EP2560955B1 (ru)
JP (1)	JP5564147B2 (ru)
KR (1)	KR101180174B1 (ru)
CN (1)	CN102844301B (ru)
AU (1)	AU2011243393B2 (ru)
BR (1)	BR112012026509B1 (ru)
CA (1)	CA2794176C (ru)
ES (1)	ES2594708T3 (ru)
HK (1)	HK1176061A1 (ru)
IL (1)	IL222491A (ru)
MX (1)	MX2012011721A (ru)
MY (1)	MY162554A (ru)
NZ (1)	NZ602612A (ru)
PH (1)	PH12012501843A1 (ru)
RU (1)	RU2536688C2 (ru)
SG (1)	SG184350A1 (ru)
UA (1)	UA107702C2 (ru)
WO (1)	WO2011132901A2 (ru)
ZA (1)	ZA201207903B (ru)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
KR101341693B1 (ko)	2011-03-16	2013-12-16	동아에스티 주식회사	생약추출물을 함유하는 퇴행성 신경질환의 치료 및 예방을 위한 조성물
KR101341692B1 (ko)	2011-03-16	2013-12-20	동아에스티 주식회사	복합생약추출물을 함유하는 당뇨병성 말초 신경병증의 치료 및 예방을 위한 조성물
KR101457789B1 (ko)	2013-02-13	2014-11-03	동아제약 주식회사	상처 치료용 필름형성 약제학적 조성물 및 그의 제조방법
CN105636946B (zh) *	2013-07-25	2017-12-19	东亚St 株式会社	制备苯甲酰胺衍生物的方法、用于制备苯甲酰胺的新型中间体以及制备新型中间体的方法
CN104230889A (zh) *	2014-08-29	2014-12-24	南京大学	环丙沙星衍生物及其制备方法与用途
KR102394635B1 (ko) *	2015-03-31	2022-05-09	(주)아모레퍼시픽	5-아다만탄-1-일-n-(2,4-다이하이드록시벤질)-2,4-다이메톡시벤즈아마이드를 함유하는 항산화 또는 항노화 조성물

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1507462A (en)	1974-03-21	1978-04-12	Gallardo Antonio Sa	N-heterocyclic substituted benzamides methods for their preparation and compositions containing them
US5057525A (en)	1981-10-01	1991-10-15	Janssen Pharmaceutica N.V.	Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives
US4962115A (en)	1981-10-01	1990-10-09	Janssen Pharmaceutica N.V.	Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives
US5137896A (en)	1981-10-01	1992-08-11	Janssen Pharmaceutica N.V.	N-(3-hydroxy-4-piperidinyl)benzamide derivatives
KR970702247A (ko)	1994-03-30	1997-05-13	고야 마사시	벤조산 화합물 및 이들의 약제로서의 용도(benzoic acid compound and use thereof as medicine)
US5864039A (en) *	1994-03-30	1999-01-26	Yoshitomi Pharmaceutical Industries, Ltd.	Benzoic acid compounds and use thereof as medicaments
TW402591B (en)	1997-07-11	2000-08-21	Janssen Pharmaceutica Nv	Monocyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
DE69938193D1 (de)	1998-11-20	2008-04-03	Hoffmann La Roche	Piperidin ccr-3 rezeptor-hemmer
EP1217000A1 (en) *	2000-12-23	2002-06-26	Aventis Pharma Deutschland GmbH	Inhibitors of factor Xa and factor VIIa
FR2861073B1 (fr) *	2003-10-17	2006-01-06	Sanofi Synthelabo	Derives de n-[heteroaryl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
KR100854211B1 (ko)	2003-12-18	2008-08-26	동아제약주식회사	신규한 옥사졸리디논 유도체, 그의 제조방법 및 이를유효성분으로 하는 항생제용 약학 조성물
KR100976063B1 (ko) *	2007-03-16	2010-08-17	동아제약주식회사	신규한 벤즈아미드 유도체 화합물 및 그의 제조방법
NZ580701A (en)	2007-04-19	2011-07-29	Dong A Pharm Co Ltd	Dpp-iv inhibitor including beta-amino group, preparation method thereof and pharmaceutical composition containing the same for preventing and treating a diabetes or an obesity
US8642772B2 (en)	2008-10-14	2014-02-04	Sk Biopharmaceuticals Co., Ltd.	Piperidine compounds, pharmaceutical composition comprising the same and its use
WO2010062959A1 (en)	2008-11-26	2010-06-03	Aryx Therapeutics, Inc.	5-ht4 receptor agonists for treating irritable bowel syndrome and colonic hypersensitivity
EP2549997A4 (en)	2010-03-24	2014-05-14	Dong A Pharm Co Ltd	PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF NON ALCOHOLIC HEALING STEATOSIS AND METHOD FOR THE PREVENTION OR TREATMENT OF NON ALCOHOLIC HEALING STEATOSIS USING THE SAME
PH12013501055A1 (en)	2010-11-24	2013-09-09	Dong A St Co Ltd	Quinoline derivative compound, method for preparing same, and pharmaceutical composition containing same
US20140155609A9 (en)	2010-11-24	2014-06-05	Dong-A St Co., Ltd.	Quinoline derivative compound, method for preparing same, and pharmaceutical composition containing same
KR101341693B1 (ko)	2011-03-16	2013-12-16	동아에스티 주식회사	생약추출물을 함유하는 퇴행성 신경질환의 치료 및 예방을 위한 조성물
KR101341692B1 (ko)	2011-03-16	2013-12-20	동아에스티 주식회사	복합생약추출물을 함유하는 당뇨병성 말초 신경병증의 치료 및 예방을 위한 조성물

2010
- 2010-04-23 KR KR1020100038039A patent/KR101180174B1/ko active IP Right Grant
2011
- 2011-04-18 SG SG2012072450A patent/SG184350A1/en unknown
- 2011-04-18 PH PH1/2012/501843A patent/PH12012501843A1/en unknown
- 2011-04-18 CN CN201180020476.6A patent/CN102844301B/zh active Active
- 2011-04-18 ES ES11772189.4T patent/ES2594708T3/es active Active
- 2011-04-18 NZ NZ602612A patent/NZ602612A/en not_active IP Right Cessation
- 2011-04-18 MY MYPI2012004698A patent/MY162554A/en unknown
- 2011-04-18 RU RU2012150037/04A patent/RU2536688C2/ru not_active IP Right Cessation
- 2011-04-18 BR BR112012026509-1A patent/BR112012026509B1/pt not_active IP Right Cessation
- 2011-04-18 JP JP2013506071A patent/JP5564147B2/ja active Active
- 2011-04-18 MX MX2012011721A patent/MX2012011721A/es not_active Application Discontinuation
- 2011-04-18 CA CA2794176A patent/CA2794176C/en active Active
- 2011-04-18 UA UAA201213255A patent/UA107702C2/ru unknown
- 2011-04-18 AU AU2011243393A patent/AU2011243393B2/en not_active Ceased
- 2011-04-18 US US13/641,867 patent/US9221790B2/en active Active
- 2011-04-18 EP EP11772189.4A patent/EP2560955B1/en active Active
- 2011-04-18 WO PCT/KR2011/002759 patent/WO2011132901A2/en active Application Filing
2012
- 2012-10-16 IL IL222491A patent/IL222491A/en not_active IP Right Cessation
- 2012-10-19 ZA ZA2012/07903A patent/ZA201207903B/en unknown
2013
- 2013-03-15 HK HK13103256.8A patent/HK1176061A1/xx not_active IP Right Cessation

Also Published As

Publication number	Publication date
CN102844301A (zh)	2012-12-26
IL222491A (en)	2016-07-31
KR20110118446A (ko)	2011-10-31
CA2794176C (en)	2015-12-15
AU2011243393B2 (en)	2014-07-17
RU2012150037A (ru)	2014-05-27
US20130085160A1 (en)	2013-04-04
ES2594708T3 (es)	2016-12-22
PH12012501843A1 (en)	2013-01-07
SG184350A1 (en)	2012-11-29
CN102844301B (zh)	2015-04-22
EP2560955A2 (en)	2013-02-27
UA107702C2 (xx)	2015-02-10
CA2794176A1 (en)	2011-10-27
MX2012011721A (es)	2012-12-17
ZA201207903B (en)	2013-06-26
JP5564147B2 (ja)	2014-07-30
KR101180174B1 (ko)	2012-09-05
IL222491A0 (en)	2012-12-31
BR112012026509B1 (pt)	2021-01-19
EP2560955A4 (en)	2013-09-11
BR112012026509A2 (pt)	2017-10-31
JP2013525344A (ja)	2013-06-20
US9221790B2 (en)	2015-12-29
RU2536688C2 (ru)	2014-12-27
AU2011243393A1 (en)	2012-10-18
HK1176061A1 (en)	2013-07-19
WO2011132901A2 (en)	2011-10-27
WO2011132901A3 (en)	2012-01-26
NZ602612A (en)	2014-11-28
MY162554A (en)	2017-06-15

Publication	Publication Date	Title
EP2560955B1 (en)	2016-06-29	Novel benzamide derivatives
KR102230383B1 (ko)	2021-03-23	히스타민 h4 수용체의 벤조이미다졸-2-일 피리미딘 조절제
EP3150578B1 (en)	2020-10-14	Novel pyrrolidine compound and application as melanocortin receptor agonist
EP2855478A1 (en)	2015-04-08	Solid forms of an antiviral compound
PT95899A (pt)	1991-09-13	Processo para a preparacao de derivados indole
EP2331506A1 (de)	2011-06-15	Neue benzamide, deren herstellung und deren verwendung als arzneimittel
FR2873691A1 (fr)	2006-02-03	Derives d'amino-piperidine, leur preparation et leur application en therapeutique
AU781837B2 (en)	2005-06-16	3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity
TW200305395A (en)	2003-11-01	Organic compounds
TW200924774A (en)	2009-06-16	Fused pyrrolidine 1,2,4-triazole derivatives as modulators of mGluR5
WO2005113499A1 (ja)	2005-12-01	インドール化合物
JP2008501732A (ja)	2008-01-24	Ｃｃｒ５拮抗剤としての化合物
HUT64759A (en)	1994-02-28	Method for producing tetrazolyl-(phenoxy-and phenoxy-alkyl-)-pyridinyl-pyridazines
EP2066626A1 (en)	2009-06-10	Azetidine derivatives as muscarinic receptor antagonists
EP1773823B1 (fr)	2013-08-21	Derives de 4-arylmorpholin-3-one, leur preparation et leur application en therapeutique
US8129413B2 (en)	2012-03-06	Crystalline forms of MC4R agonist and process for synthesis
WO1998022443A1 (fr)	1998-05-28	Derives de n-(imidazolylbutyle) benzenesulfonamide ayant une activite antithrombotique
WO2020261160A1 (en)	2020-12-30	Methods and intermediates for preparing hydrochloride salt of 5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide
JPH08169830A (ja)	1996-07-02	５−ｈｔ４受容体作動薬
BR112016027352B1 (pt)	2023-08-22	Composto de pirrolidina, composição farmacêutica compreendendo o referido composto e uso do mesmo
HU211665A9 (hu)	1995-12-28	Az átmeneti oltalom az 1-19. igénypontokra vonatkozik.
JP2006111531A (ja)	2006-04-27	１−［２−（４−ベンジル−４−ヒドロキシ−ピペリジン−１−イル）−エチル］−３−（２−メチル−キノリン−４−イル）−尿素塩。

Legal Events

Date	Code	Title	Description
2013-01-25	PUAI	Public reference made under article 153(3) epc to a published international application that has entered the european phase	Free format text: ORIGINAL CODE: 0009012
2013-02-27	17P	Request for examination filed	Effective date: 20121109
2013-02-27	AK	Designated contracting states	Kind code of ref document: A2 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
2013-07-31	DAX	Request for extension of the european patent (deleted)
2013-09-11	A4	Supplementary search report drawn up and despatched	Effective date: 20130808
2013-09-11	RIC1	Information provided on ipc code assigned before grant	Ipc: C07D 211/26 20060101ALI20130802BHEP Ipc: C07D 211/16 20060101AFI20130802BHEP Ipc: C07D 401/06 20060101ALI20130802BHEP Ipc: A61K 31/435 20060101ALI20130802BHEP
2015-04-15	17Q	First examination report despatched	Effective date: 20150312
2016-01-18	GRAP	Despatch of communication of intention to grant a patent	Free format text: ORIGINAL CODE: EPIDOSNIGR1
2016-02-17	INTG	Intention to grant announced	Effective date: 20160119
2016-05-23	GRAS	Grant fee paid	Free format text: ORIGINAL CODE: EPIDOSNIGR3
2016-05-27	GRAA	(expected) grant	Free format text: ORIGINAL CODE: 0009210
2016-06-29	AK	Designated contracting states	Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
2016-06-29	REG	Reference to a national code	Ref country code: GB Ref legal event code: FG4D
2016-06-30	REG	Reference to a national code	Ref country code: CH Ref legal event code: EP
2016-07-15	REG	Reference to a national code	Ref country code: AT Ref legal event code: REF Ref document number: 808985 Country of ref document: AT Kind code of ref document: T Effective date: 20160715
2016-07-27	REG	Reference to a national code	Ref country code: IE Ref legal event code: FG4D
2016-08-04	REG	Reference to a national code	Ref country code: DE Ref legal event code: R096 Ref document number: 602011027778 Country of ref document: DE
2016-10-18	REG	Reference to a national code	Ref country code: SE Ref legal event code: TRGR
2016-10-25	REG	Reference to a national code	Ref country code: LT Ref legal event code: MG4D
2016-10-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160929 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2016-11-07	REG	Reference to a national code	Ref country code: NL Ref legal event code: MP Effective date: 20160629
2016-11-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160930 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2016-12-15	REG	Reference to a national code	Ref country code: AT Ref legal event code: MK05 Ref document number: 808985 Country of ref document: AT Kind code of ref document: T Effective date: 20160629
2016-12-22	REG	Reference to a national code	Ref country code: ES Ref legal event code: FG2A Ref document number: 2594708 Country of ref document: ES Kind code of ref document: T3 Effective date: 20161222
2017-01-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20161029 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2017-02-28	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20161031
2017-03-27	REG	Reference to a national code	Ref country code: FR Ref legal event code: PLFP Year of fee payment: 7
2017-03-30	REG	Reference to a national code	Ref country code: DE Ref legal event code: R097 Ref document number: 602011027778 Country of ref document: DE
2017-05-05	PLBE	No opposition filed within time limit	Free format text: ORIGINAL CODE: 0009261
2017-05-05	STAA	Information on the status of an ep patent application or granted ep patent	Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT
2017-05-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2017-06-07	26N	No opposition filed	Effective date: 20170330
2017-06-15	STAA	Information on the status of an ep patent application or granted ep patent	Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT
2017-08-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160929 Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2017-11-30	REG	Reference to a national code	Ref country code: CH Ref legal event code: PL
2018-01-24	REG	Reference to a national code	Ref country code: IE Ref legal event code: MM4A
2018-01-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2018-02-28	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170418 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430
2018-03-27	REG	Reference to a national code	Ref country code: FR Ref legal event code: PLFP Year of fee payment: 8
2018-04-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170418
2018-09-28	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: MT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170418
2018-10-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2019-06-28	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20110418
2019-10-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: CY Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20160629
2019-11-29	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2020-03-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160629
2020-10-19	REG	Reference to a national code	Ref country code: DE Ref legal event code: R082 Ref document number: 602011027778 Country of ref document: DE Representative=s name: D YOUNG & CO LLP, DE
2023-07-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: IT Payment date: 20230414 Year of fee payment: 13 Ref country code: FR Payment date: 20230407 Year of fee payment: 13 Ref country code: ES Payment date: 20230505 Year of fee payment: 13 Ref country code: DE Payment date: 20230419 Year of fee payment: 13
2023-08-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: SE Payment date: 20230413 Year of fee payment: 13
2023-10-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: GB Payment date: 20230417 Year of fee payment: 13
2024-11-05	REG	Reference to a national code	Ref country code: DE Ref legal event code: R119 Ref document number: 602011027778 Country of ref document: DE
2024-12-03	REG	Reference to a national code	Ref country code: SE Ref legal event code: EUG
2024-12-25	GBPC	Gb: european patent ceased through non-payment of renewal fee	Effective date: 20240418
2025-01-10	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20241105
2025-01-17	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20240418
2025-01-20	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20240430
2025-01-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20240418 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20240430 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20241105